Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring. Pregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT1R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction. Increased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of AT1R and pg91phox subunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in AT1R and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension. Dysfunction of AMPK-regulated AT1R expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.

中文翻译：

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子代母体高果糖暴露对高血压编程中的异常AMPK调节血管紧张素AT ₁ R表达和SIRT1介导的线粒体生物发生在RVLM

组织氧化应激，交感神经激活和营养感应信号与成人胎儿起源的高血压密切相关，尽管它们在高血压程序中的相互作用尚不清楚。基于程序性高血压的孕妇高果糖饮食（HFD）模型，我们测试了AMP活化蛋白激酶（AMPK）调节血管紧张素1型受体（AT1R）表达和sirtuin1（SIRT1）依赖性线粒体生物发生的功能障碍的假说有助于年轻后代程序性高血压的组织氧化应激和交感神经兴奋。怀孕的雌性大鼠在妊娠和哺乳期间被随机分配为接受正常饮食（ND）或HFD（60％果糖）食物。断奶后ND和HFD后代均恢复了ND状态，并在6至12周龄期间监测血压（BP）。在8周大的时候，ND和HFD后代口服辛伐他汀或二甲双胍；或脑微输注氯沙坦。通过尾套法在意识状态下监测血压。通过Western印迹分析法测定了前额腹外侧延髓（RVLM）中的营养感应分子，AT1R，NADPH氧化酶亚基，线粒体生物发生标记。RVLM氧化应激通过荧光探针二氢乙啶测定，脂质过氧化通过丙二醛测定。线粒体DNA拷贝数通过实时定量聚合酶链反应确定。年轻的HFD后代表现出收缩压升高，血浆去甲肾上腺素水平升高和交感性血管舒张活动。RVLM中交感运动前神经元所在的活性氧（ROS）水平也升高，NATPH氧化酶AT1R和pg91phox亚基的蛋白表达增加，而超氧化物歧化酶2减少；和抑制线粒体生物发生的转录因子，过氧化物酶体增殖物激活的受体γ共激活因子α（PGC-1α）和线粒体的转录因子A（TFAM）。母体HFD还减弱了年轻后代RVLM中AMPK的磷酸化和SIRT1的蛋白表达。向年轻的HFD后代口服HMG-CoA还原酶抑制剂辛伐他汀或AMPK激活剂二甲双胍可逆转母体HFD编程的AT1R升高，SIRT1，PGC-1α和TFAM降低；减轻RVLM中ROS的产生，并减轻交感神经兴奋和高血压。